title: A new alpha 1-antitrypsin mutation, Thr-Met 85, (PI Zbristol) associated with novel electrophoretic properties.
abstract: A new AAT allele (PI Zbristol) has been discovered in a woman with an obstetric history of three perinatal deaths from fulminant liver disease and no living offspring. She and her father were both PI M1Zbristol heterozygotes. The Zbristol protein is active as a proteinase inhibitor but appeared to be deficient in the plasma to about the same degree as the S protein in MS heterozygotes. It focuses on the basic side of Z and lacks the normal pattern of secondary isoforms associated with the commonly occurring AAT variants and migrates faster than normal on an SDS electrophoresis gel. The Zbristol mutation was found to be a C to T transition at codon 85 changing ACG (Thr) to ATG (Met). This disrupts the N-glycosylation site starting at Asn 83 preventing glycosylation at residue 83 in the PI Zbristol protein and explains the protein isoelectric focusing and SDS gel electrophoresis results. An analysis of haplotypes in the propositus and her father indicated that the Zbristol mutation occurred on the common M1(Val 213) genetic background. The new mutation also led to the generation of an NlaIII restriction endonuclease recognition site. Cell lines from two offspring tested for the presence of this NlaIII site revealed that one had the variant and the other did not. Thus, the relationship between Zbristol and fulminant liver disease in the offspring is unclear.
authors.affiliation: MRC Human Biochemical Genetics Unit, Galton Laboratory, University College London.
authors.forename: J U
authors.initials: JU
authors.lastname: Lovegrove
authors.forename: S
authors.initials: S
authors.lastname: Jeremiah
authors.forename: G T
authors.initials: GT
authors.lastname: Gillett
authors.forename: I K
authors.initials: IK
authors.lastname: Temple
authors.forename: S
authors.initials: S
authors.lastname: Povey
authors.forename: D B
authors.initials: DB
authors.lastname: Whitehouse
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D004252:DNA Mutational Analysis; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007525:Isoelectric Focusing; D008297:Male; D008715:Methionine / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012967:Sodium Dodecyl Sulfate; D013912:Threonine / Q000235:genetics*; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D013912:Threonine; D012967:Sodium Dodecyl Sulfate; D008715:Methionine